Notch1 gene mutations target KRAS G12D-expressing CD8⁺ cells and contribute to their leukemogenic transformation

Background: Endogenous oncogenic Kras induces a highly penetrant acute T-cell lymphoblastic leukemia/lymphoma (T-ALL). Results: Up-regulation of NOTCH1 signaling, through either overexpression of surface NOTCH1 or acquired gain-of-function mutations, is involved in both T-ALL initiation and progression. Conclusion: Notch1 mutations contribute to leukemogenic transformation of normal T-cells. Significance: Our data provide a rationale to target both NOTCH1 and RAS signaling for T-ALL treatment.